This background information is provided for the purpose of making information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should it be construed, that any of the information disclosed herein constitutes prior art against the present invention.
Serotonin (5-hydroxytryptamine, 5-HT) receptors are implicated in a wide variety of physiological functions in both the central and peripheral nervous systems.
5-HT2C receptors have been implicated in a wide variety of diseases/conditions including obesity, anxiety, depression, obsessive compulsive disorder, schizophrenia, migraine and erectile dysfunction. See e.g., Dunlop, J., et al., CNS Drug Reviews 12:167-177 (2006). Consequently, this subtype of receptors is a valuable target for drug discovery. (7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole} (commonly known as WAY-163909) a novel 5-HT2C receptor selective agonist has receive considerable attention. See e.g., Dunlop, J., et al., CNS Drug Reviews 12:167-177 (2006). WAY-163909 has been found to play a role in obesity, psychotic-like behavior and depression. See e.g., Dunlop, J., et al., CNS Drug Reviews 12:167-177 (2006). Accordingly, in addition to developing future therapeutics, there exists a need to develop to tools to study two 5-HT receptor (5-HTXRS) systems, the 5-HT2AR and 5-HT-2CR. The 5-HT2AR and 5-HT-2CR receptors are in oppositional control with 5-HT2AR antagonists and 5-HT-2CR agonists exerting similar effects and acting in synergy on behaviors such as impulse control and reactivity to cocaine-associated cues. See e.g., Cunningham, K. A, et al., ACS Chem. Neurosci. 4:110-121 (2013).
Like many G-protein coupled receptors (GPCRs), these receptors are thought to exist and/or function as both homo- and/or heteromeric dimers. See e.g., Manica, F., et al., EMBO Reports 9(4), 363-369 (2008). The differing roles of these types of dimers is not fully understood, and the development of molecules that can serve as tools to biochemically and/or pharmacologically distinguish between the types of dimers is needed.
Furthermore, there exists a need for the development of probe molecules that can be used to investigate receptor location and relationship with other GPCRs. Moreover, there is a need to develop ligands that can be linked to other molecules including a second ligand, a reporter molecule (e.g., fluorescent dyes) or immobilization agents (e.g. biotin). A further challenge is to identify locations on known 5-HTxR ligands that will allow for linking such groups without altering the ligands' binding and/or activity and successfully synthesize such compounds.